Experimental data indicate large between-organs variations in rates of synthesis of tissue-type plasminogen activator (t-PA), which may reflect important differences in the capacity for constitutive and stimulated t-PA release from the vascular endothelium. In this report we describe a new multiple-organ experimental in vivo model for simultaneous determinations of net release/uptake rates of t-PA across the coronary, splanchnic, pulmonary, and hepatic vascular beds. In eleven intact anesthetized pigs, blood samples were obtained simultaneously from the proximal aorta, coronary sinus, pulmonary artery, and portal and hepatic veins. Plasma flows were monitored separately for each vascular region. Total plasma t-PA was determined by ELISA with a porcine t-PA standard. Regional net release/uptake rates were defined as the product of arteriovenous concentration gradients and local plasma flows. The net release of t-PA across the splanchnic vascular bed was very high, with a mean output of 1,919 ng total t-PA X min-1 (corresponding to 90 ng per min and 100 g tissue). The net coronary t-PA release was 68 ng X min-1 (30 ng X min-1 X 100 g"1)- Pulmonary net fluxes of t-PA were variable without any significant net t-PA release. The net hepatic uptake rate was 4,855 ng X min-1 (436 ng X min-1 X 100 g-1). Net trans-organ changes of active t-PA mirrored those of total t-PA. The results demonstrate marked regional differences in net release rates of t-PA in vivo. The experimental model we present offers new possibilities for evaluation of regional secretion patterns in the intact animal.
References
1
Emeis JJ.
Mechanisms involved in short-term changes in blood levels of tissue-type plasminogen activator. in: Tissue-type Plasminogen Activator (t-PA): Physiological and Clinical Aspects.
Kluft C.
ed.
Boca Raton; CRC Press: 1988. 02. pp. 21-35
3
Wun T-C,
Capuano A.
Spontaneous fibrinolysis in whole human plasma. Identification of tissue activator-related protein as the major plasminogen activator causing spontaneous activity in vitro. J Biol Chem 1985; 260: 5061-5066
4
Jem C,
Selin L,
Jem S.
In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. Thromb Haemost 1994; 72: 285-291
5
Jem S,
Selin L,
Bergbrant A,
Jem C.
Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72: 588-94
7
Keber D,
Blinc A,
Fettich J.
Increase of tissue plasminogen activator in limbs during venous occlusion: a simple hemodynamic model. Thromb Haemost 1990; 64: 433-437
8
Emeis JJ.
Regulation of the acute release of tissue-type plasminogen activator from endothelium by coagulation products. in: Plasminogen activation in fibrinolysis in tissue remodeling, and in development.
Brakman P,
vKluft C.
(eds).
Ann NY Acad Sci. 1992. 667. 249-258
9
Padro T,
van denHoogen,
Emeis JJ.
Distribution of tissue-type plasminogen activator (activity and antigen) in rat tissues. Blood Coagulation Fibrinolysis 1990; 01: 601-608
10
van den Eijnden-SchrauwenY,
Kooistra T,
de VriesREM,
Emeis JJ.
Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vivo: evidence of a dynamic storage pool. Blood 1995; 85: 3510-3517
12
Bålfors E,
Häggmark S,
Ariola Jr S,
Biber B,
Pontén J,
Reiz S.
In vitro analysis of thermal transport in coronary sinus thermodilution catheters. Clin Physiol 1983; 03: 469-476
13
Aneman A,
Pontén J,
Fändriks L,
Eisenhofer G,
Friberg P,
Biber B.
Splanchnic and renal sympathetic activity in relation to hemodynamics during isofluran administration in pigs. Anesth Analg 1995; 80: 135-142
14
Rånby M,
Nguyen G,
Scarabin PY,
Samama M.
Immunoreactivity of tissue plasminogen activator and of its inhibitor complexes. Thromb Haemost 1989; 61: 409-414
16
Wallen P,
Bergsdorf N,
Rånby M.
Purification and identification of two structural variants of porcine tissue plasminogen activator by affinity adsorption on fibrin. Biochim Biophys Acta 1982; 719: 318-328
17
Wiman B,
Mellbring G,
Rånby M.
Plasminogen activator release during venous stasis and exercise as demonstrated by a new specific assay. Clin ChimActa 1983; 127: 279-288
18
Rånby M,
Sundell IB,
Nilsson TK.
Blood collection in strong acidic citrate anticoagulant used in a study of dietary influence on basal t-PA activity. Thromb Haemost 1989; 61: 511-516
19
Huisman LGM,
Meijer P,
van GriensvenJ,
Kluft C.
Evaluation of the specificity of antigen assays for plasminogen activator inhibitor 1: comparison of two new commercial kits. Fibrinolysis 1992; 06 (Suppl. 03) 87-88
20
Simpson AJ,
Booth NA,
Moore NR,
Bennet B.
The platelet and plasma pools of plasminogen activator inhibitor (PAI-1) vary independently in disease. Br J Haematol 1990; 75: 543-548
24
Eliasson M,
Evrin P-E,
Lundblad D,
Asplund K,
Rånby M.
Influence of gender, age and sampling time on plasma fibrinolytic variables and fibrinogen. Fibrinolysis 1993; 07: 316-323
25
Rahr HB,
Sorensen JV,
Larsen JF,
Svendsen JensenF,
Bredahl C.
Plasminogen activators and plasminogen activator inhibitor in portal blood from patients with and without gastric malignancy. Scand J Gastroenterol 1996; 31: 170-174
26
Gough SCL,
Smyllie J,
Sheldon J,
Rice PJS,
Grant PJ.
The anatomical distribution of plasma fibrinolytic activity in man during cardiac catheterization. Thromb Haemost 1992; 68: 442-447
27
Chandler WL,
Levy WC,
Stratton JR.
The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation 1995; 92: 2984-2994
29
Chomiki N,
Henry M,
Alessi MC,
Anfosso F,
Juhan-Vague I.
Plasminogen activator inhibitor-1 expression in human liver and healthy or atherosclerotic vessel walls. Thromb Haemost 1994; 72: 44-53
30
Hart DA.
Hepatic regulation of fibrinolysis in normal and disease states. in: Fibrinolysis in disease. Molecular and hemovascular aspects of fibrinolysis.
Glas-Greenwalt P.
ed.
Boca Raton; CRC Press: 1995. pp 43-54
32
Otter M,
Kuiper J,
van BerkelThJC,
Rijken DC.
Mechanisms of tissue-type plasminogen activator (tPA) clearance by the liver. Ann NY Acad Sci 1992; 667: 431-442
35
Wing LR,
Hawksworth GM,
Bennet BBooth.
Clearance of t-PA, PAI-1 and t-PA-PAI-1 complex in an isolated perfused rat liver system. J Lab Clin Med 1991; 117: 109-114
36
Kuiper J,
Otter M,
Voorschuur AH,
van ZonneveldAJ,
Rijken DC,
van BerkelThJC.
Characterization of the interaction of a complex of tissue- type plasminogen activator and plasminogen activator inhibitor type 1 with rat liver cells. Thromb Haemost 1995; 74: 1298-1304
37
Brommer EJP.
The level of extrinsic plasminogen activator (t-PA) during clotting as a determinant of the rate of fibrinolysis: Inefficiency of activators added afterwards. Thromb Res 1984; 34: 109-115